The present invention is related to processes for synthesis of a tetrasubstituted enamide and asymmetric reduction of the tetrasubstituted enamide to form the chiral amide, and intermediate compounds obtained during the process. These processes are useful in the synthesis of pharmaceutically useful compounds, particularly those described in WO 03/077847.
In WO 03/077847, synthesis of these compounds is achieved by non-stereoselective means and resolution of the isomers by chiral HPLC, which is not amenable to large scale production and produces excessive amounts of the undesired isomer.
US 2004/0019216 and Huang et al., JACS 125:6653-6655 (2003) disclose copper catalyzed carbon-heteroatom bond formation, and particularly carbon-nitrogen bond formation between a nitrogen of an amide or amine moiety and the activated carbon of an aryl, heteroaryl or vinyl halide or sulfonate. Wallace et al., Org. Lett. 5(24): 4749-4752 (2003) describe the formation of enamides by palladium catalyzed coupling of enol triflates with amides, carbamates and sulfonamides. WO 03/066570 is directed to formation of N-aryl amides and N-aryl amines by reaction of a compound with a primary or secondary amino or amido group with an arylating compound, in the presence of a weak base and a transition metal catalyst comprising a Group 8 metal and at least one carbene-containing ligand. U.S. Pat. No. 6,235,936 and U.S. Pat. No. 6,465,693 are respectively concerned with arylation and vinylation of hydrazines, hydrazones, hydroxylamines and oximes by reacting the appropriate aryl or vinyl compound having an activated carbon with a leaving group with a transition metal catalyst to form a carbon-heteroatom bond. U.S. Pat. No. 5,817,877 is directed to preparation of an organic amine having at least one unsaturated group by contacting an unsaturated organic sulfonate with a reactant amine in the presence of base and a transition metal catalyst containing a Group 8 metal and a chelating ligand, e.g., a Group 15-substituted arylene or Group 15-substituted metallocene. U.S. Pat. No. 6,235,938 is directed to preparing N-aryl amine compounds by reacting a compound having a amino group with an arylating compound in the presence of a base and a transition metal catalyst comprising a Group 8 metal and a chelating bisphosphine ligand having at least one sterically hindered alkyl substituent. U.S. Pat. No. 6,323,366 is directed to preparation of primary aryl or vinyl amines by combining an activated aryl or vinyl group and an imine in the presence of a transition metal catalyst and transforming the resulting N-aryl imine to the desired primary aryl or vinyl amine. U.S. Pat. Nos. 6,100,389 and 5,977,361 relate to the preparation of N-aryl amine, and amide compounds. Anderson et al., J. Org. Chem. 68:9563-9573 (2003) describe Pd-catalyzed amination of aryl nonaflates (ArOSO2—(CF2)3CF3). Yin et al., JACS 124:6043-6048 (2002) describe Pd-catalyzed amidation of aryl halides.
The present invention involves palladium catalyzed coupling of primary amides with vinyl tosylates. Use of the vinyl tosylate avoids the use of vinyl triflates, which is not amenable to large scale production. Still further, the tosylate intermediate is crystalline and easy to handle. The process is a stereoselective enolization and coupling that produces the Z isomer in high purity.
The present invention involves asymmetric rhodium-catalyzed hydrogenation of tetrasubstituted enamides. This reaction involves high enantioselectivity. Still further, the use of a Lewis Acid such as BF3.MeOH (or some other source of BF3) permits the hydrogenation to be carried out at low H2 pressure and reaction temperature, providing a safety and cost advantage with less catalyst than would otherwise be necessary. Still further, in a preferred embodiment, the present invention sets two chiral centers in the same reaction. Overall, the synthetic route of the present invention provides the additional benefit of not requiring the use of azide.
U.S. Pat. No. 6,465,664 is directed to methods for asymmetric 1,4-hydrogenation to cyclic and acyclic enoates and enones using a catalyst comprising copper and an asymmetric bidentate bisphosphine ligand. U.S. Pat. No. 5,489,682 is directed to catalytic asymmetric reduction of enamines with chiral metal catalysts selected from Groups 3, 4, 5, or 6, lanthanide and actinides. U.S. Pat. No. 5,292,893; U.S. Pat. No. 5,491,233 and U.S. Pat. No. 5,442,119 are directed to a catalytic asymmetric hydrogenation process for hydrogenation of tri-substituted olefins and enamines.
The present invention makes use of a chiral, transition metal catalyst. The use of chiral catalysts for stereoselective hydrogenations is described in Tang et al., Chem. Rev. 103: 3029 (2003); Blaser et al., Adv. Synth. Catal. 345: 103 (2003); and Blaser et al., Applied Catalysis A: General, 221:119 (2001). EP 0 770 085, U.S. Pat. No. 5,907,045, U.S. Pat. No. 6,077,958, U.S. Pat. No. 6,586,357 describe chiral phosphines and complexes between these diphosphines and transition metals comprising an aromatic pentatomic biheterocyclic system, including
and their use in stereo controlled reductions. These ligands are also described in Benincori et al., J. Org. Chem. 65:2043-2047 (2000). EP 1 070 075 is directed to atropo-isomeric chiral phosphorated ligands having C1, symmetry, and organometallic complexes containing phosphorated ligands in optically active form and their use in stereoselective organic syntheses.
WO 00/29370, U.S. Pat. No. 6,566,552, U.S. Pat. No. 6,545,165, US 2002/0165408 address processes for production of L-carnitine by enantioselective reduction of an oxo group to the optically active hydroxyl group, employing [(+)TMBTP)Ru(p-cymene) I2].
WO 01/57014, US 2003/0158422, US 2003/0158423, US 2003/0171602, EP 1 127 886 are directed to the multistep production of a δ-lactone from an acyl halide preferably employing a Ruthenium (R) MeOBIPHEP catalyst in the enantioselective reduction.
WO 03/078399 is directed to asymmetric hydrogenation of hexahydroquinoline salts using an iridium or rhodium catalyst comprising a chiral diphosphine ligand of either of the formulae below:

The use of HBF4 in the hydrogenation of pyridine containing enamides with Rh catalysts is described in Döbler, Tetrahedron: Asymmetry 7:117 (1996). Still further Shriver discloses the use of a Lewis acid to promote Rh catalyzed hydrogenation of ethylene (not an asymmetric reaction), in Inorganic Chemistry 17:3069 (1978).
The present invention provides for a palladium catalyzed coupling of a primary amide with a vinyl tosylate in the presence of a palladium catalyst.
The present invention also provides for asymmetric hydrogenation of tetrasubstituted enamides with chiral rhodium catalysts.
Still further, the present invention provides for particular crystal forms of N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethylpyridin-2-yl)oxy]propanamide, a product which may be produced from the coupling and hydrogenation of the present invention.